Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer-related deaths in the world. The most common alterations in lung cancer include activating mutations in ras genes and inactivating mutations in the p53 gene. Lung tumor cells with p53 mutations or deletions often develop resistance to chemotherapy and radiation therapy, leading ultimately to the death of the patients. Notably, such p53-deficient cancer cells are susceptible to apoptosis by the proapoptotic tumor suppressor, Par-4.
Par-4 is a tumor suppressor protein that induces apoptosis in diverse cancer cells but not in normal cells. Par-4 is ubiquitously expressed in normal cells and tissues, but is sequestered by an intermediary filament protein, vimentin, and hence, circulating levels of Par-4 are generally low. If it were secreted by normal cells at appreciably higher levels than normal, certain cancer cells would be susceptible to its effects. Extracellular Par-4 binds a receptor GRP78, which appears only on the cancer cell surface, and induces apoptosis by caspase-dependent mechanisms. In contrast, normal cells express low to undetectable levels of basal or inducible cell-surface GRP78 and are resistant to apoptosis by extracellular Par-4.
Therefore, there is a need for compounds that are Par-4 secretagogues and promote the secretion of Par-4 which in turn promotes apoptosis in cancer cells and metastatic cells.